We have observed that ethanol increases the rate of decay of post-tetanic potentiation (PTP) at a synapse in the abdominal ganglion of Aplysia californica. Upon repeated exposure to ethanol, the ethanol effect disappears so that tolerance may be said to have developed. This tolerance lasts for at least 12 hours after the last exposure to ethanol. The rate of decay of PTP is also influenced by changing the temperature of the preparation. Between 20 degrees and 12 degrees the rate of decay of PTP changes very little. However, if the temperature of the preparation is reduced to 10 degrees or less, the rate of decay of PTP is strikingly reduced. When the ganglion is maintained at low temperature (e.g., 11 degrees rather than the usual 15 degrees) for 4 hours, tolerance develops to the effect of lowering the temperature on the rate of decay of PTP. The mechanism for the development of tolerance to ethanol and to reduction of temperature may be related. Our working hypothesis is that the rate of decay of PTP is determined by the state of fluidity of the component of the presynaptic membrane which regulates the probability of transmitter release which is, in turn, augmented during PTP. At the transition temperature the fluidity of this component of the membrane is reduced so that it relaxes more slowly to the resting condition prolonging the decay of PTP; whereas, ethanol has the opposite effect. Tolerance presumably involves a change in membrane components such that they no longer behave in the manner observed in a normal preparation. Our working hypothesis is that tolerance involves a change in critical membrane components, possibly lipids. We seek indirect and direct evidence of this hypothesis.